WJ C World Journal of

Cardiology
Submit a Manuscript: http://www.wjgnet.com/esps/ World J Cardiol 2014 August 26; 6(8): 728-743
Help Desk: http://www.wjgnet.com/esps/helpdesk.aspx ISSN 1949-8462 (online)
DOI: 10.4330/wjc.v6.i8.728 © 2014 Baishideng Publishing Group Inc. All rights reserved.

TOPIC HIGHLIGHT

WJC 6th Anniversary Special Issues (1): Hypertension

Prehypertension: Underlying pathology and therapeutic
options

Sulayma Albarwani, Sultan Al-Siyabi, Musbah O Tanira

Sulayma Albarwani, Sultan Al-Siyabi, Department of Physiol- tial pathophysiological processes associated with PHTN,
ogy, College of Medicine and Health Sciences, Sultan Qaboos abridges current intervention strategies and suggests
University, Muscat 123, Oman investigating the value of using the “Polypill” in prehy-
Musbah O Tanira, Department of Pharmacology and Clinical pertensive subjects to ascertain its potential in delaying
Pharmacy, College of Medicine and Health Sciences, Sultan Qa-
(or preventing) CVD associated with raised blood pres-
boos University, Muscat 123, Oman
Author contributions: Albarwani S, Al-Siyabi S and Tanira MO sure in the presence of other risk factors.
solely contributed to this paper.
Correspondence to: Dr. Sulayma Albarwani, Department of © 2014 Baishideng Publishing Group Inc. All rights reserved.
Physiology, College of Medicine and Health Sciences, Sultan
Qaboos University, P.O.Box 35, Muscat 123, Key words: Prehypertension; Renin-angiotensin system;
Oman. salbarwani@squ.edu.om Therapeutic lifestyle changes; Polypill
Telephone: +968-24141108 Fax: +968-24143514
Received: December 17, 2013 Revised: June 8, 2014 Core tip: There is a current debate over the ideal
Accepted: June 14, 2014
means of intervening in prehypertension. Since it is
Published online: August 26, 2014
the cardiovascular risk that constitute the basis for in-
tervention in both prehypertension and hypertension,
the review discusses the following points, that: (1)
categorizing blood pressure levels is based on mere 20
Abstract mmHg brackets; hence this doctrine may be re-visited
to include other cardiovascular risk factors to catego-
Prehypertension (PHTN) is a global major health risk rize patients regardless of their blood pressure level;
that subjects individuals to double the risk of cardio- (2) investigating the therapeutic potential of interven-
vascular disease (CVD) independent of progression to ing in all pathophysiological processes associated with
overt hypertension. Its prevalence rate varies consider- prehypertension; and (3) ascertaining the therapeutic
ably from country to country ranging between 21.9%
value of the “Polypill” in prehypertensives as means of
and 52%. Many hypotheses are proposed to explain
primary prevention.
the underlying pathophysiology of PHTN. The most
notable of these implicate the renin-angiotensin system
(RAS) and vascular endothelium. However, other pro-
Albarwani S, Al-Siyabi S, Tanira MO. Prehypertension: Un-
cesses that involve reactive oxygen species, the inflam-
derlying pathology and therapeutic options. World J Cardiol
matory cytokines, prostglandins and C-reactive protein
2014; 6(8): 728-743 Available from: URL: http://www.wjg-
as well as the autonomic and central nervous systems
net.com/1949-8462/full/v6/i8/728.htm DOI: http://dx.doi.
are also suggested. Drugs affecting RAS have been
org/10.4330/wjc.v6.i8.728
shown to produce beneficial effects in prehypertensives
though such was not unequivocal. On the other hand,
drugs such as β-adrenoceptor blocking agents were not
shown to be useful. Leading clinical guidelines suggest
using dietary and lifestyle modifications as a first line SEARCH AND ARTICLE COLLECTION
interventional strategy to curb the progress of PHTN;
however, other clinically respected views call for using
METHOD
drugs. This review provides an overview of the poten- Initially, PubMed and Scopus were searched using the

WJC|www.wjgnet.com 728 August 26, 2014|Volume 6|Issue 8|

 Albarwani S et al . Prehypertension: Pathophysiology and treatment
key words prehypertension, epidemiology, and treatment
(as such or in the form of derived terms as appropriate)
alone and in combination, were used to identify a set
of primary articles. Other searches using pertinent key
words were conducted as required; such was particularly
utilized during search for pathophysiologically-related
publications. For example, treatment + prehypertension
led to renin-angiotensin system, which led to angioten-
sin converting enzyme system, angiotensin converting
enzyme inhibitors, angiotensin receptor blockers and so
on. To the resulted articles we added our own collection.
Reviews were used as another source to include more ar-
ticles. All searches were limited to English language.
The main aim of this review was to provide an overall
understanding of the current status of the medical pro-
fession opinion on prehypertension and to map the so
far recommended or suggested therapeutic strategies. It
also reflected on other potential therapeutic options. The
selection of cited references was made to serve that aim.
CONCEPTUAL OVERVIEW
Definitions
The concept of prehypertension (PHTN) was introduced
in 1939 by Robinson and Brucer who were first to draw
attention to the range of blood pressure (BP) between
120-139 mmHg (systolic) and 80-89 mmHg (diastolic) as
being of value in determining clinically overt hyperten-
sion (HTN)[1]. Almost three decades later, the same BP
range was given the name “borderline hypertension”[2],
then the name changed to “high-normal blood pressure”
in 1997[3]. The name “prehypertension” was given in
2003[4]. The nomenclature went further by some authors[5]
who categorized BP levels between 130-139/85-89
mmHg (the upper half of PHTN range) as “Stage 2”
PHTN. Also, the upper half of the HTN range was given
the name of “high normal” blood pressure by the Euro-
pean Society of Hypertension/the European Society of
Cardiology[6].
HTN is defined as a systolic/diastolic pressure level
of ≥ 140/90 mmHg)[7,8]. HTN is a major world health
problem and is among the most prevalent chronic condi-
tions with rates that reach up to 70% of adult population
in some countries[9] and is on the increase[10]. HTN has
been identified as the leading global risk factor for disease
burden[11] and it is considered to be the most important
modifiable risk factor for coronary heart disease, stroke,
congestive heart failure and end-stage renal failure[12].
Salient issues pertaining to blood pressure and
cardiovascular risk
Prior to start the discussion on the main topic of this
review i.e prehypertension, there are a number of issues
that are of significant value to this topic and they address
the relationship of changes in BP and their correlation
with cardiovascular (CV) morbidity and mortality. These
are; the J-blood pressure curve concept; the central ver-
sus peripheral blood pressure relation with CV events;
and the complex interaction of different antihypertensive
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drugs on blood pressure and cardiac hemodynamics. A
brief account of each of these follows.
The J-blood pressure curve concept and cardiovascular
risk
The “J-curve” concept describes the shape of the rela-
tionship between BP and the risk of CV morbidity or
mortality[13]. Some authors consider the J-curve to be
more correlated with diastolic blood pressure (DBP) than
systolic blood pressure (SBP)[14] since most of coronary
blood flow occurs in diastole[15]. Three pathophysiologic
mechanisms have been proposed to explain the existence
of a J-curve are: (1) low DBP could be an additional risk
factor to coexisting or underlying poor health or chronic
illness leading to increasing morbidity and mortality; (2)
low DBP could be caused by an increased pulse pressure
reflecting advanced vascular disease and stiffened large
arteries; and (3) over-aggressive antihypertensive treat-
ment could lead to too-low DBP and thus hypo-perfu-
sion of the coronaries resulting in coronary events[13].
The J-curve concept is in line with the thought that
BP has a continuous relationship with CV events such as
myocardial infarction, stroke, sudden death, heart failure
and peripheral artery disease as well as of end-stage renal
disease[16-20] even at values such as 110-115 mmHg for
SBP and 70-75 mmHg for DBP[21,22].
Central systolic versus peripheral systolic blood
pressure and cardiovascular events
In adults, peripheral SBP (pSBP) exceeds central (aortic)
SBP (cSBP) by about 10 mmHg or more[23]. This differ-
ence is greater in younger subjects, during exercise and
is affected by drug therapy[23]. Because cSBP and cPP are
more closely related to the load on the heart and pulsatile
stress on the coronary arteries than pSBP, they are sug-
gested to be better predictors of CV events[24,25]. Addi-
tionally, it may be highlighted that the heart, kidneys, and
major arteries supplying the brain are exposed to aortic
rather than peripheral pressure. Therefore, there is a ra-
tionale to believe that CV events may be more related to
central rather than brachial pressure[26].
The increase in central pressure from diastolic to sys-
tolic values is determined by the compliance of the aorta
as well as the ventricular stroke volume. A high central
pulse pressure (PP) is considered to be a marker of in-
creased artery stiffness and represents a well-established
independent predictor of CV morbidity and mortal-
ity[27-29] in hypertensive individuals and even in those con-
sidered as having normal BP[30]. PP significantly predicts
major adverse CV events including unstable angina pec-
toris, myocardial infarction, coronary revascularization,
stroke, or death[31]. An independent correlation between
aortic PP and coronary artery disease was established in
men, along with age and hypercholesterolaemia[32,33]. The
late decrease in DBP after the age of 60, associated with
a continual rise in SBP, is consistent with increased large
artery stiffness. Higher SBP, if left untreated, may accel-
erate large artery stiffness and thus perpetuate a vicious
cycle[21].
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 Albarwani S et al . Prehypertension: Pathophysiology and treatment
Indeed, central pressure was found to be more (than
peripheral pressure) correlated with indicators such as
carotid intima-media thickness[24,34,35] and left ventricular
mass[35-37]. Also, aortic pulse pressure was found to be sig-
nificantly and independently correlated with angiographi-
cally determined coronary artery stenosis[38] and more
related to CV events than brachial pressure[24,39-41] and
responds differently to certain drugs[25,42]. For example, it
was found that the b-blocker, atenolol, is inferior to other
major anti-hypertensive drug classes in preventing CV
events. b-blockers exert differential effects on brachial vs
central pressure which may help to explain the adverse
findings with atenolol in outcome studies and provides
support for the hypothesis that drugs which lower central
pressure the most will be more effective[43-48].
Antihypertensive drugs and cardiovascular events
The interaction of antihypertensive drugs on BP and
coronary hemodynamics (and hence CV events) is com-
plex. For example, not all antihypertensive drugs have
similar effects on pulse pressure. Blockers of the renin-
angiotensin system, calcium antagonists and diuretics im-
prove arterial compliance and thus lower SBP more than
DBP and therefore diminish pulse pressure. In contrast
b-blockers, because they decrease heart rate, increase
stroke volume would have a less favorable effect on pulse
pressure than the other drugs. Yet, decreased heart rate
may allow for more prolonged diastolic perfusion of the
coronary vascular bed and vice versa; whereas, short-acting
calcium antagonists and other arteriolar vasodilators (such
as hydralazine, minoxidil) are prone to cause myocardial
ischemia in susceptible patients[49].
Antihypertensive drugs that reduce left ventricular
hypertrophy (LVH) and hypertensive vascular disease
are more effective over the long term in improving coro-
nary flow reserve than drugs that have little or no effect.
Thus, blockers of the renin-angiotensin system, calcium
antagonists as well as the diuretics, have been shown to
reduce LV hypertension[50] and hypertensive vascular dis-
ease[51-53] and improve arterial compliance[54] better than
b-blockers.
EPIDEMIOLOGY OF PHTN
Many studies in various countries were performed to
determine the magnitude of the PHTN rate. These have
revealed that PHTN prevalence is considerable and it var-
ies widely from country to country. For example, preva-
lence rate averages at 21.9% in China[55], at 32.8% in the
Netherlands[56], at 34% in Taiwan[57], at 37% in the United
States[58], at 40% in Ghana[59], at 48.2% in Oman[60] and at
52% in Iran[61]. Men[57-59,61] and blacks[62] are more likely to
be affected than women or whites; respectively.
CARDIOVASCULAR RISK OF PHTN
PHTN is not only a caveat to develop overt HTN, but it
is a major health risk on its own also. Prehypertensives
were repeatedly reported to be subjected to approximate-
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ly double the risk of CVD independent of progression
to HTN[58,63] in addition to other cardiovascular complica-
tions[64-66].
PATHOPHYSIOLOGIC CHANGES
ASSOCIATED WITH RAISED BP
This part of the review is intended to discuss briefly the
significant pathophysiologic changes associated with the
progressive increase in BP to provide the scientific prem-
ise for currently recommended interventions or another
that is recommended by this review.
INVOLVEMENT OF THE
RENIN-ANGIOTENSIN SYSTEM (RAS)
Effects of RAS on cardiovascular system in general
Angiotensin Ⅱ, an active peptide of the RAS, causes
increase in BP and enhances oxidation of the low-
density lipoprotein via stimulation of its type 1 recep-
tor (AT1)[67,68]. It appears that it acts in this respect by
inhibiting NAD(P)H oxidase-mediated oxygen synthesis
and enhances antioxidant superoxide dismutase activity
in the cardiovascular system and decreases nitric oxide
(NO) bioavailability. The latter effect may be responsible,
at least in part, for the beneficial effects of drugs inhibit
RAS activity such as angiotensin converting enzyme
inhibitors (ACEIs) or angiotensin Ⅱ type 1 receptor
blockers (ARBs) that may act, eventually, by enhancing
NO availability[69-71]. However, RAS blockade provides
additional protective effect on cardiovascular function
that cannot be solely explained by mere reduction of BP
which is the action mediated by increasing NO availabil-
ity[72].
In this context, it may be added that angiotensin-
converting enzyme 2 (ACE2) converts angiotensin I to
angiotensin (Ang)-1-9, that can be converted by ACE to a
shorter peptide, Ang-1-7, which has an intrinsic vasodila-
tor activity[73,74]. ACE2 have been described to be a potent
negative regulator of RAS, counterbalancing the multiple
functions of ACE, thus, it plays a protective role in the
CV system and other organs[75].
Also, chronic activation of the RAS was shown to
underlie HTN, insulin resistance, cardiac and renal dis-
ease, and polycystic ovarian syndrome and it serves as a
link between obesity and low-grade systematic inflamma-
tion[76-80]. In addition, it is suggested that RAS contributes
to the atherosclerotic process through angiotensin Ⅱ,
which acts as a proinflammatory mediator directly induc-
ing atherosclerotic plaque development and heart remod-
eling and exacerbate endothelial dysfunction[81,82]. On the
other hand, blockade of RAS can offer protection from
RAS-related metabolic diseases including diabetes[83-88].
The statement by Demirci et al[72] is further enforced
by the observation that the ACE gene may be a determi-
nant of serum ACE levels, but it does not appear to con-
fer susceptibility to essential hypertension[89], since there
are many factors that influence the genetic make-up of
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 Albarwani S et al . Prehypertension: Pathophysiology and treatment
blood pressure[90]. In addition, other environmental fac-
tors[91] may be involved in determining BP. Therefore, the
possibility of drugs interfering in the RAS to be addition-
ally interfering with any of these other factors cannot be
eliminated.
Effect of RAS on development of hypertension
The first report on the potential of early intervention to
prevent HTN was in 1990[92]. The authors showed that
inhibiting RAS by captopril (an ACEI) for two weeks
may intervene in the progression of HTN in young “pre-
hypertensive” spontaneously hypertensive rats (SHRs).
Later, other studies have shown that transient inhibition
of the renin-angiotensin system from two weeks of age
in SHRs, either with ACEIs or with ARBs, diminishes the
increase in BP for up to 21 wk after cessation of treat-
ment[93]. While others reported that permanent treatment
of SHRs from conception onwards with ACEIs com-
pletely prevented hypertension[94,95].
The ARBs losartan was reported to have beneficial
effect in humans[96] and rats[97,98] similar to that of cap-
topril in SHRs, specifically, as shown by another study
that transient use of losartan resulted in a long-lasting
improvement of arterial contractility, an effect that was
linked to endothelium-dependent vasodilatation[92,98].
Paradoxically, other authors showed that decreased
BP is accompanied by severe disruption of the normal
vascular architecture of intrarenal arteries[99]. These au-
thors concluded that, apparently interference with RAS
during a crucial stage of development in SHRs can initi-
ate this disturbance and may cause intrarenal vascular
smooth muscle hyperplasia, suggesting the involvement
of another trophic factor that is inhibited by angiotensin
II under physiologic conditions. Such led other workers[72]
to suggest that the efficacy of antihypertensive treatment
is also influenced by age and the hypertensive stage of
the investigate animals.
INVOLVEMENT OF VASCULAR
ENDOTHELIUM
The association between RAS and endothelium-dependent
pathways in PHTN was suggested by more than one ob-
servation. It was shown that dysfunctional NO synthesis
in PHTN may be a source of oxygen free radicals or reac-
tive oxygen species (ROS) which may be an additive factor
to develop overt HTN[100]. Jameson et al[101] reported that,
endothelium-dependent relaxation of prehypertensive
SHRs mesenteric arteries was impaired. Later, interleukin-
1β (which induces inducible NO Synthase) was shown to
cause a lower production of NO and a reduced genera-
tion of cGMP in these animals[102]. This observation was
followed by demonstrating that lower NO level corre-
lated with increased SBP in the same species[103]. Such was
related to impaired NO production alone[104] or combined
with an enhanced ROS activity which may contribute to
progression of PHTN to HTN[105]. All these effects in-
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dicate that endothelial vasodilator capacity is impaired in
PHTN[106].
INVOLVEMENT OF REACTIVE OXYGEN
SPECIES (ROS)
It is stated above that ROS may add to developing overt
HTN. Therefore, it is not surprising that antioxidant
deficiency has been long implicated in HTN pathogen-
esis[107-109]; whereas, antioxidant treatment to reduce oxi-
dative stress was shown to prevent development of HTN
in SHRs[110]. Many studies have demonstrated that enhanced
production of plasma free radicals may impair the physio-
logic function of vascular endothelium[111-113]. An action that
may lead to increase in BP. Recently, the rationale for antioxi-
dant trials in PHTN was reviewed by Nambiar et al[114].
INVOLVEMENT OF THE INFLAMMATORY
PROCESS: PROSTGLANDINS AND
C-REACTIVE PROTEIN
Inflammation was also implicated in the development of
HTN and in endothelial dysfunction either as a primary
or a secondary event[115]. Inflammation, indicated by
C-reactive protein (C-RP) level, was used to predict HTN
among PHTN subjects[116,117]. In addition, prostaglandin
E2 (an inflammatory cytokine) was particularly shown to
enhance norepinephrine-pressor response in PHTN; an
effect that was abolished by indomethacin (a prostaglan-
din synthesis inhibitor)[118].
INVOLVEMENT OF THE AUTONOMIC
NERVOUS SYSTEM
Eyal et al[119] suggested that α-adrenoceptors of SHRs are
in a basic state of excitation even prior to the onset of
overt HTN, i.e., in PHTN. Prior to this observation, Fuji-
moto et al[120] demonstrated that β-adrenoceptor-mediated
relaxation of arteries, in the same species, was diminished
before and during development of HTN. The diminished
relaxation may be because of defective hyperpolarization
induced by these receptors[121]. In the same rat species,
both the M3 cholinoceptors- and P2y-mediated relax-
ation was not altered[122] ruling out involvement of any
other component of the autonomic nervous system apart
from the sympathetic. However, β-blockers, compared to
ACEIs, did not improve resistance arteries function after
two years of use in human[123,124].
The underlying mechanism for the sympathetic in-
volvement was also indicated by the presence of sub-
sensitive presynaptic α2-adrenceptors which may lead to
exaggerated norepinephrine secretion[125], an effect that
may have a causal relevance to development of HTN[126].
Similarly, the β2-adrenceptor-mediated facilitation of
neurogenic pressor response was found to be enhanced
in prehypertensive SHRs, which may contribute to devel-
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 Albarwani S et al . Prehypertension: Pathophysiology and treatment
opment of HTN[127].
INVOLVEMENT OF CENTRAL
MECHANISMS
An impaired baroreceptor control of vascular resistance
was implicated in SHRs[128] and such was thought to be a
primary defect[129]. In humans, baroreflex was not found
to be altered, but plasma norepinephrine positively cor-
related to BP and associated with subsensitive α- and
[130]
β-adrenoceptors .
Another explanation of the symapthetic overactive
state in PHTN/HTN was postulated by Kotchen et al[131].
It is based on the observation that brain NO, as a neu-
rotransmitter, reduces sympathetic output, and systemic
angiotensin Ⅱ activates NO-producing neurons. SHRs
show higher gene expression of nNOS, probably, as a
compensatory mechanism for increased BP. That hy-
pothesis was supported by the finding that hypothalamic
angiotensin Ⅱ-sensitive neurons activity was greatly en-
hanced in PHTN[132], and that the central component of
the baroreflex was also impaired[133].
INVOLVEMENT OF OTHER MECHANISMS
Other than RAS pathways should be investigated since
not all the beneficial effects attributed to anti-RAS drugs
(in HTN and PHTN) can be solely understandable by its
mere reduction in BP. For example, RAS is activated by
common comorbidity including type 2 diabetes, hyperin-
sulinemia and excess weight as well as it can be activated
by a diet rich in carbohydrates and fats. Two clinical tri-
als[134,135] have shown that ACEIs decrease the risk of
developing type 2 diabetes in patients with HYN and/or
vascular disease.
THERAPEUTIC OPTIONS OF
PREHYPERTENSION
Rationale for therapeutic intervention in PHTN
PHTN and HTN are associated with a number of fac-
tors such as increased age, male gender, increased C-RP
level and waist circumference[117,136]. These factors are
positively correlated with the development of HTN[117].
Yet and despite the clear relationship between HTN and
PHTN, treating HTN is unequivocally accepted, but the
debate over the use of the term PHTN itself as a clinical
category[137] or what type of intervention to be used in
this case has not yet been concluded. The main reasons
raising the thought of therapeutically intervening in pre-
hypertensive subjects can be summarized as follows: (1)
elevated systolic BP is the most important risk factor for
cardiovascular, cerebrovascular, and renal disease[4,16,138];
(2) there is a strong association of cardiovascular mortal-
ity risk with BP[16]; (3) it is expected that many individuals
with PHTN will, with time, become overt hypertensive
patients[139]; and (4) for normotensive population, it was
calculated that SBP increases at an average rate of about
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0.5 mmHg/year[137].
Current suggested intervention strategies in PHTN
In principle, intervening in PHTN is a form of primary
prevention, which can be enacted in more than one way.
One is by the use of proven and safe drugs; another is by
inducing individual behavioral changes. The latter is an
attractive option because of its inherent “natural” appeal,
perceived low cost, simplicity and safety though may not
be sustainable.
Primary prevention strategies that are directed to-
wards the individual necessitate screening all individuals
in order to identify those who are over a certain “thresh-
old”. That process is followed by subjecting individuals at
risk to an appropriately “tailored” intervention to each of
them which incurs high cost. In addition, risk prediction
in primary prevention remains imprecise and may not re-
flect long-term risk[140].
At the community level, primary prevention may be
endorsed by passing health policies, encouraging ben-
eficial cultural attitudes and/or imposing environmental
changes. This approach is more likely to have a greater
impact on individual’s health[141-144].
At present, it is agreed in principle, that prehyperten-
sive subjects should be treated. However, there is a po-
larizing controversy on the means of intervention. Two
main strategies are recommended; one is based on “Ther-
apeutic Lifestyle Changes (TLCs)”[4], and the second is
based on using antihypertensive monodrug therapy[5].
TLCS
Previous[3] and current guidelines[5] advocate specific
lifestyle modifications for prehypertensives. The most
recent recommendations (JNC7 report)[4] are as follows:
(1) maintain body mass index between 18.5 and 24.9 kg/
m2; this is expected to reduce SBP by 5 to 20 mmHg for
each 10-kg reduction in weight; (2) consume a diet rich
in fruits and vegetables, as well as low-fat dairy products;
this is expected to reduce SBP by 8 to 14 mmHg; (3) re-
strict sodium to no more than 6 g of table salt per day;
this is expected to reduce SBP by 2 to 8 mmHg; (4) walk
briskly at least 30 min per day or engage in other regular
aerobic physical activity; this is expected to reduce SBP
by 4 to 9 mmHg; and (5) reduce alcohol consumption;
this reduces SBP by 2 to 4 mmHg.
Evidence for therapeutic effectiveness of lifestyle
modifications
The JNC 7 lifestyle changes are focused on weight loss,
dietary restriction and exercise, which were supported by
abundant clinical evidence. For example, weight loss[145],
and salt restriction [146] have been shown to improve
PHTN. Maintaining a body mass index between 18.5 and
24.9 kg/m2 is expected to reduce SBP by 5 to 20 mmHg
for each 10-kg reduction in weight[16].
Weight loss has been shown to be the most effective
lifestyle modification strategy for prevention of hyper-
tension[147]. Reductions in BP occur even without attain-
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 Albarwani S et al . Prehypertension: Pathophysiology and treatment
ment of normal body mass index. In a meta-analysis
of 25 randomized, controlled trials, weight loss of 1 kg
was associated with approximately 1 mmHg reduction in
SBP and DBP in individuals with HTN[148]. Addition of
antihypertensive medication has been shown to have an
effect on BP reduction that is additive to that achieved by
weight loss alone[148,149]. However, it has been shown that
the type of medication prescribed may decrease the abil-
ity of the patient to lose weight[147].
Dietary pattern changes, in general[150] or specifically
prescribed such as the Dietary Approaches to stop hyper-
tension (DASH) plan[151,152] which uses a diet rich in fruits,
vegetables, legumes, nuts, and low-fat dietary products
and low in saturated fats, induced a significant lowering
of BP. Adhering to the DASH diet can reduce BP by 8-14
mmHg, an effect that was augmented even further when
dietary sodium was restricted. The OmniHeart Collab-
orative Research Group study[153] in which the DASH diet
was modified to provide more protein and unsaturated
fat and less carbohydrate, impressive reductions of BP
were also achieved. The TOHP trial[147], in a substudy of
the DASH trial also showed that by reducing sodium in-
take to less than 100 mmol in your daily diet, in addition
to dietary changes provided greater benefit than either
approach alone[154].
Similarly, there is ample evidence that exercise, inde-
pendent of weight loss, decreases BP[154-157]. A number of
clinical trials demonstrated that increased physical activity
can lower BP independent of any effect on body weight,
although this finding is not universal[158-160]. However, two
meta-analyses concluded clearly that physical activity in-
dependently lowers BP[161,162]. In one of these meta-anal-
yses, 27 of 50 studies reported results in nonhypertensive
subgroups, which presumably include a large proportion
of participants with PHTN[162]. Exercise alone has been
associated with a 30% reduction in cardiac risk, making it
similar to statin and antihypertensive interventions[163-166].
Hence, a number of studies have been performed to ex-
amine the effects of aerobic and/or resistance exercise
on BP in hypertensive, prehypertensive, and normoten-
sive groups, and a recent review has examined the rel-
evant findings[167].
Nevertheless, some trials have shown that TLCs to
have a modest and unsustainable impact to reduce CVD
events when tested in large, long-term trials[152,168]. This
observation has been challenged by the PREMIER tri-
al[169] which studied the combined effects of diet, physical
activity, and weight reduction in three groups of prehy-
pertensive and hypertensive subjects over an 18-mo pe-
riod. Although all three groups demonstrated significant
reductions in BP in both prehypertensive and hyperten-
sive subjects, the amount of decrease in the group given
relatively minimal counseling was both surprising and
gratifying in view of the previous difficulties with obtain-
ing long-term behavioural changes to improve the car-
diovascular risk status. These findings encourage adding
counseling as an important early augmenting interven-
tion to lifestyle modifications that may sustain beneficial
therapeutic effect. This view is further supported with
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the findings of the largest population-based experience of
lifestyle modification as a strategy to reduce cardiovascular
risk factors, CVD, and mortality. The study used a com-
prehensive community-level approach that encompassed
the health and other services like voluntary organizations,
local media, businesses including the Food Industry and
changes to public policy. It demonstrated a reduction in
mortality from coronary artery disease by 55% in men
and by 68% in women over a 20-year period[170]. Further-
more, in a recent randomized clinical trial[171] it was found
that subjects with increased BP who participated in an
automated online self-management program resulted in
improved BP among prehypertensive or hypertensive sub-
jects. These findings emphasize the need to involve pa-
tients for a more sustainable outcome. Similar results were
obtained in overt hypertensive patients, who, in a prospec-
tive cohort study received repeated nonpharmacological
recommendations to follow low-salt and low-calorie diets
and to do physical activities[172]. This study concluded that
adherence to follow low-salt and low-calorie diets is asso-
ciated with clinically relevant long-term BP reduction and
better hypertension control in clinical setting.
Although the evidence on reducing alcohol intake
and reduction in BP is equivocal[173,174], a meta-analysis of
trials in this respect with many of the analysed trials in-
cluded prehypertensives[175] suggest that reducing alcohol
intake can independently lower SBP.
THERAPEUTIC INTERVENTION WITH A
MONODRUG THERAPY
All concluded studies that have been attempting to treat
PHTN used one drug that affects the RAS in the form
of ACEIs, ARBs or renin inhibitors. The use of other
monotherapies such as β-blockers, was not shown to be,
compared to ACEIs, effective in improving resistance ar-
teries function after two years of use in human[123,124]. The
involvement of RAS in PHTN and HTN was discussed
earlier. This part of the review summarizes the outcome
of clinical trials using drugs that affect RAS in this respect.
Clinical trials with drugs affecting RAS: ongoing clinical
trials
Two clinical trials are ongoing: (1) the first trial is the
PREVER-Prevention trial[176], a controlled randomized,
double-blind trial designed to include individuals with
PHTN given chlorthalidone 12.5 mg plus amiloride 2.5
mg or placebo. The study is to investigate if early use
of drugs in individuals with PHTN may prevent cardio-
vascular events, target-organ damage and the incidence
of overt HTN. In the 2nd International Conference on
Prehypertension and Cardiometabolic Syndrome (January
31 - February 3, 2013; Barcelona, Spain) the trial co-prin-
cipal investigator (Fuchs FD) announced that PREVER
has finished enrollment of 1053 patients. According to
the study design, patients who are still prehypertensive
after three months of recommended lifestyle changes are
randomized to a low-dose combination of chlorthalidone
733 August 26, 2014|Volume 6|Issue 8|
 Albarwani S et al . Prehypertension: Pathophysiology and treatment
plus amiloride or to placebo. Preliminary results from the
study[177] indicate that 659 (77%) of subjects remained
prehypertensive and were randomized according to the
study protocol; another 7.5% had abnormal lab values,
and 6.2% had progressed to developing HTN, while 9%
had seen their BP drop to within normal values; and (2)
The second trial is the Chinese High Normal Blood Pres-
sure (CHINOM) trial. The study has finished enrollment
of 10689 patients with BP in the range of 130-139/85-89
mmHg and at least one other cardiovascular disease
risk factor (but no established diabetes, renal or hepatic
dysfunction, or history of stroke or CVD). The trial
randomized patients to one of three parallel treatment
groups: telmisartan 40 mg, indapamide 1.5 mg, or, in the
third group, placebo or a combination pill of hydrochlo-
rothiazide 12.5 mg, triamterene 12.5 mg, dihydralazine
12.5 mg, and reserpine 0.1 mg. The primary end point of
the study is combined CV events (nonfatal stroke, non-
fatal MI, and CVD death), while secondary end point ad-
dresses new-onset hypertension and new-onset diabetes.
In the above mentioned conference, it was announced
that the CHINOM trial is still awaiting the first results
which may be still several years away. However, baseline
characteristics of study subjects are showing that 70%
of subjects enrolled actually have more than one cardio-
vascular risk factor with metabolic syndrome being the
most common. More than three-quarters of participants
are overweight or obese, 42% have high triglycerides, and
over one-third have a family history of hypertension[177].
Clinical trials with drugs affecting RAS: concluded
clinical trials
The first clinical trial was the TRial Of Preventing HY-
pertension (TROPHY)[178,179] which examined whether
early treatment of PHTN justified pharmacologic in-
tervention with the use of an ARB (candesartan 16 mg
daily) in HTN. TROPHY hypothesis to examine whether
ARBs may be useful to treat PHTN was based on the
following: (1) PHTN is a strong independent predictor
of cardiovascular events; (2) growth factors mediated
by stimulation of the sympathetic nervous system[180]
and excess activity of RAS[181] tend to promote vascular
hypertrophy by direct as well as hemodynamic effects.
Antihypertension treatment with ACIs or ARBs, but not
with b-blockers, has been reported to cause regression of
arteriolar hypertrophy[123,124]; and and (3) despite intensive
community efforts to promote healthy lifestyle, the preva-
lence of PHTN[182] in the United States is increasing.
Over a period of four years of TROPHY study, it was
found that stage 1 HTN developed in nearly two thirds
of patients with untreated PHTN (the placebo group).
Treatment of PHTN with candesartan appeared to be
well tolerated and reduced the risk of incident HTN dur-
ing the study period. The authors concluded that, treat-
ment of PHTN appears to be feasible.
Although the observations in this study indicate that
candesartan may ameliorate BP in prehypertensives, a
comment by the authors stated that they do not advocate
WJC|www.wjgnet.com
treatment of the 25 million people (in the United States)
with prehypertension. They added that additional studies
will be needed to ascertain whether this or other strate-
gies involving early pharmacologic treatment of PHTN
would positively affect clinical outcomes.
Another trial is the PHARAO study[183] which demon-
strated that ramipril (an ACEI) given to prehypertensives
reduced the risk of HTN by 34.4% compared to those
not taking antihypertensive drugs; however, no differ-
ences were found in cardiovascular or cerebrovascular
events. The study concluded that prehypertensives are
more likely to progress to overt HTN than those with
optimal or normal BP when treated with ACEIs.
A third trial, on the other hand, concluded that phar-
macological therapy is indicated for some patients with
PHTN who have specific comorbidities, including diabe-
tes mellitus, chronic kidney disease and coronary artery
disease[184], while another trial[185] did not support the use
of antihypertensive drugs in “normotensive” subjects
and that, ARBs might offer less protection against myo-
cardial infarction than ACEs.
Most recently, the AQUARIUS trial [186] examined
the effect of aliskiren (a renin inhibitor) on progression
of coronary atherosclerosis in a double-blind, random-
ized, multicenter trial study. It concluded that among
participants with PHTN and coronary artery disease, the
use of aliskiren compared with placebo did not result
in improvement or slowing of progression of coronary
atherosclerosis and that their findings do not support the
use of aliskiren for regression or prevention of progres-
sion of coronary atherosclerosis.
INTERVENTION WITH MULTIDRUG
FORMULATIONS: SHOULD THE
“POLYPILL” BE CONSIDERED IN PHTN?
What is the “Polypill”?
The “Polypill” is a multidrug formulation with modified
drug combinations containing drugs such aspirin, statins,
β-blockers, ACEIs and ARBs; all of which are of proven
value in reducing CVD morbidity and mortality. Approxi-
mately, half of the decline in cardiovascular mortality ob-
served in developed countries during the last two decades is
attributable to medical therapy using these types of drugs[187].
The introduction of the Polypill idea was not intend-
ed for use in PHTN, rather it was for reducing the bur-
den of CVD in economically disadvantaged individuals
to reduce cost and improve adherence. It was meant to
be applied to entire or large segments of the population.
The reasons behind innovating the Polypill (see below)
were, in effect, the same as those for intervening with
PHTN, the authors suggest considering to include prehy-
pertensives in future Polypill clinical trials to ascertain the
potential benefit of using the Polypill in these subjects.
Rationale behind the polypill composition
Some of the main relevant reasons for introducing the
734 August 26, 2014|Volume 6|Issue 8|
 Albarwani S et al . Prehypertension: Pathophysiology and treatment
Polypill are summarized as follows: (1) cardiovascular
disease is the major cause of death and disability glob-
ally and affects approximately half of all individuals
over their lifetimes[140]. CVD has increased in developing
countries, and by the year 2020, 80% of the global CVD
mortality is predicted to occur in low- and middle-income
countries[188]; (2) world population is threatened by in-
creasing obesity, sedentary lifestyles, and diabetes mellitus
rates[187]. If these conditions are added to increased BP,
primary intervention strategies directed towards commu-
nity rather than individuals become of more therapeutic
value; (3) nine to ten potentially modifiable risk factors
account for 90% of the attributable risk for myocardial
infarction and stroke, with similar estimates in all major
regions of the world[189,190]; and (4) the prevalence of low
risk factor burden is on the increase. In the US it was
only 4.4% during 1971-1975, 10.5% during 1988-1994,
and 7.5% during 1999-2004[191].
In addition to the above reasons, it has been shown
that monodrug therapeutic intervention in PHTN has
yielded mixed results, with some researchers have shown
benefits[184] while others have not[185]. It seems that the
existence of comorbidities determines how a prehyper-
tensive subject is likely to respond to pharmacological
intervention[192]. Hence, the authors propose to consider
including prehypertensives in future clinical trial of the
Polypill to investigate how much benefit they may gain by
multidrug therapeutic intervention.
Clinical evidence for the polypill effectiveness
Two randomized, placebo-controlled trials investigated
the therapeutic effect of the polypill. The first was con-
ducted in 2011[193]. It was an international randomised
placebo-controlled trial of a four-component combina-
tion pill (“polypill’’) in people with raised cardiovascular
risk (over 7.5%, determined by the Framingham risk)
using data on age, gender, BP, total cholesterol, HDL
cholesterol, diabetes status, and cigarette smoking status.
It contained aspirin 75 mg, lisinopril 10 mg, hydrochlo-
rothiazide 12.5 mg, and simvastatin 20 mg or to placebo.
The drug combination was associated with a 9.9-mmHg
drop in SBP and a 0.8-mmol/L reduction in LDL choles-
terol over a 12-wk treatment period.
The second clinical trial[194] studied a polypill con-
tained amlodipine 2.5 mg, losartan 25 mg, hydrochloro-
thiazide 12.5 mg and simvastatin 40 mg; but contained
no aspirin. The pill was given for 12 wk. The treatment
showed reductions mean systolic (17.9 mmHg) and DBP
(9.8 mmHg) and LDL blood level was reduced by 1.4
mmol/L.
CONCLUSION
PHTN is a major health challenge that requires extra-
attention. The “challenge” resides in finding the answer
to “how/what” should be the intervention strategy (or
strategies) that may best reduce its health impact.
In the search for a “strategy” to intervene in prehy-
pertension, a number of considerations may be notewor-
WJC|www.wjgnet.com
thy and can be summarized as follows: (1) the rationale
behind therapeutic intervention in hypertensive, and,
indeed, prehypertensive subjects is to prevent (or de-
lay progression of) cardiovascular events and mortality
caused by these conditions. Yet, it is equally accepted
that presence of other comorbidities such as diabetes
mellitus, obesity, dyslipidemia, etc. in addition to ethnic,
age and gender differences should also be accounted
for when an intervention strategy considered; (2) the
term PHTN is based on “defining” HTN itself, which
is established on a 20-mmHg per brackets. Yet, BP is
confounded by many factors such as circadian rhythms,
food intake, stress, exercise, emotional state etc. leading
to “variable BP variability”[137,195]; (3) based on the above
two points, it is plausible to suggest that, categorizing and
staging of subjects on basis of BP alone may need to be
re-considered. It may be more clinically useful to contain
factors, together, that cause BP variability to “stage” BP
levels as well as to calculate cardiovascular risk factors.
Such, may produce new terminologies or new defini-
tions of PHTN and HTN. Consequently, an intervention
strategy may not be “one-size-fits-all”, and may neces-
sitate more than one intervention. Different strategies (or
combination thereof) may be considered. For example,
males may require a different strategy from females since
differences between genders have been reported in overt
HTN[196,197]. Similarly, children PB progression differs
from that of adults[198] and, thus may need a different
intervention strategy. Furthermore, different ethnicities
have shown different patterns in both progression of
their BP as well as response to therapy and, hence, they
may need different intervention strategies[199-202]; (4) the
first-line treatment for prehypertensives should be based
on adoption of a healthy lifestyle, especially if there are
other associated risk factors such as obesity, dyslipid-
emia, pre-diabetes or diabetes, excessive alcohol intake,
sedentary lifestyle and smoking[203] as well as salt-intake
restriction[152]. It is desirable if TLCs would be adopted
by government and NGOs and may be “enforced” as a
“policy” that is directed (in a way similar to the antismok-
ing campaign) towards changing community behavior; and
(5) if pharmacologic means will be used, such should not
be confined to drugs affecting RAS, other drugs may be
investigated to ascertain whether it is the mere reduction
in BP that is benefitting prehypertensives or other effects.
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